- Email: [email protected]
What went wrong in the natalizumab trials?
Comment
regulatory regimens.24,25 This will be one of the most important debates to get right in contemporary public health.
11
Simon Chapman
13
University of Sydney, Sydney 2006, New South Wales, Australia [email protected]
14
12
SC is on the boards of the Cancer Council NSW and Action on Smoking and Health (Australia), and is editor of Tobacco Control. 1 2
3
4
5
6
7
8
9
10
Bero L. Implications of the tobacco industry documents for public health and policy. Annu Rev Public Health 2003; 24: 267–88. Hirschhorn N. Tobacco documents bibliography. Galen Digital Library, University of California at San Francisco, April 27, 2005: http://www. library.ucsf.edu/tobacco/docsbiblio.html (accessed Sept 29, 2005). Assunta M, Fields N, Knight J, Chapman S. Care and feeding: the Asian environmental tobacco smoke consultants program. Tob Control 2004; 13 (suppl 2): ii4–12. Chapman S, Carter SM. “We are anxious to remain anonymous”: the use of third party scientific and medical consultants by the Australian tobacco industry. Tob Control 2003; 12 (suppl 31): iii1–37. Fields N, Chapman S. Chasing Ernst Wynder: 40 years of Philip Morris efforts to influence a leading scientist. J Epidemiol Community Health 2003; 57: 571–78. Anonymus. B & W problem lab: how to better estimate future environment for tobacco industry and B&W growth. April 27, 1977: http://legacy.library.ucsf.edu/tid/kfr83f00 (accessed Sept 29, 2005). Philip Morris International. Smoking and health: a clear and consistent message. 2004: http://www.philipmorrisinternational.com/pages/eng/ smoking/S_and_H.asp (accessed Sept 29, 2005). British American Tobacco. Smoking and health. Aug 23, 2005: http:// www.bat.com/OneWeb/sites/uk__3mnfen.nsf/vwPagesWebLive/ ED9E7B3E9270D92880256BF40003317F?opendocument&SID=&DTC= (accessed Sept 29, 2005). Hammond D, Collishaw NE, Callard C. Secret science: tobacco industry research on smoking behaviour and cigarette toxicity. Lancet 2006; 367: 749–53. Bialous SA, Yach D. Whose standard is it, anyway? How the tobacco industry determines the International Organization for Standardization (ISO) standards for tobacco and tobacco products. Tob Control 2001; 10: 96–104.
15
16 17
18
19 20
21
22
23 24 25
Shiffman S, Pillitteri JL, Burton SL, Rohay JM, Gitchell JG. Smokers’ beliefs about “Light” and “Ultra Light” cigarettes. Tob Control 2001; 10 (suppl 1): i17–23. Henningfield J, Pankow J, Garrett B. Ammonia and other chemical base tobacco additives and cigarette nicotine delivery: issues and research needs. Nicotine Tob Res 2004; 6: 199–205. Chapman S. “Keep a low profile”: pesticide residue, additives, and freon use in Australian tobacco manufacturing. Tob Control 2003; 12 (suppl 3): iii45–53. Department of Health and Ageing, Australian Government. Australian cigarette ingredient information. 2004: http://www.health.gov.au/ internet/wcms/Publishing.nsf/Content/health-pubhlth-strateg-drugstobacco-ingredients.htm (accessed Sept 29, 2005). Webb W (Philip Morris). Status of Marlboro development program. July 12, 1984: http://legacy.library.ucsf.edu/tid/gmr98e00 (accessed Sept 29, 2005). King W, Borland R, Christie M. Way-out developments at BATCO. Tob Control 2003; 12: 107–08. Foulds J, Ramstrom L, Burke M, Fagerstrom L. Effect of smokeless tobacco (snus) on smoking and public health in Sweden. Tob Control 2003; 12: 349–59. Campbell-Johnson Ltd. A public relations strategy for the Tobacco Advisory Council. Nov 20, 1978: http://legacy.library.ucsf.edu/tid/ uus39e001984 (accessed Sept 29, 2005). Wynder EL, Hoffmann D. Reduction of tumorigenicity of cigarette smoke. JAMA 1965; 192: 88–94. DiFranza JR, Savageau JA, Rigotti NA, et al. Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control 2002; 11: 228–35. Carter SM, Chapman S. Smoking, health and obdurate denial: the Australian tobacco industry in the 1980s. Tob Control 2003; 12 (suppl 3): iii23–30. Cummings KM, Morley CP, Hyland A. Failed promises of the cigarette industry and its effect on consumer misperceptions about the health risks of smoking. Tob Control 2002; 11 (suppl 1): i110–117. Vagg R, Chapman S. Nicotine analogues: a review of tobacco industry research interests. Addiction 2005; 100: 701–12. Borland R. A strategy for controlling the marketing of tobacco products: a regulated market model. Tob Control 2003; 12: 374 –82. Callard C, Thompson D, Collishaw N. Transforming the tobacco market: why the supply of cigarettes should be transferred from for-profit corporations to non-profit enterprises with a public health mandate. Tob Control 2005; 14: 278–83.
What went wrong in the natalizumab trials? A 42-year-old woman in Colorado had a history of intermittent episodes of neurological dysfunction and was diagnosed with relapsing-remitting multiple sclerosis. She was treated with interferon-1 alfa, but continued to have episodes of neurological dysfunction and was enrolled into a clinical trial of natalizumab, a novel immunomodulatory agent. Unfortunately, she was one of three patients who developed progressive multifocal leucoencephalopathy and she died.1–3 According to her case report, her autopsy revealed no evidence of multiple sclerosis. She had no objective evidence of central nervous system inflammation at any time: her spinal tap analysis at the time of diagnosis was normal, and she never had gadolinium-enhancing lesions on any of her multiple brain MRI scans.1 The clinical 708
history, brain imaging, and autopsy findings were more consistent with migraines and infarcts than with relapsing-remitting multiple sclerosis. Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Until recently, no reliable measure of CNS inflammation or demyelination existed. Diagnosis was therefore established on clinical criteria alone. Specifically, multiple sclerosis was defined by two unexplained episodes of neurological dysfunction separated in time and by neuroanatomical region, plus the presence of one or more objective neurological deficits on examination.4,5 These criteria were devised for research rather than clinical purposes, at a time when most multiple sclerosis trials were done at academic centres and, because of their www.thelancet.com Vol 367 March 4, 2006
Comment
www.thelancet.com Vol 367 March 4, 2006
Rights were not granted to include this image in electronic media. Please refer to the printed journal
Science Photo Library
vagueness, require clinical expertise in neurology and multiple sclerosis to use. Diagnostic criteria for multiple sclerosis have since been revised to reflect developments in technology and an improved understanding of disease pathogenesis. However, the revisions have only served to broaden the definition of multiple sclerosis, rather than improve the specificity of diagnosis. Physicians may now diagnose multiple sclerosis on the basis of either the old clinical criteria or when a single clinical attack is accompanied by objective evidence of CNS inflammation and demyelination on brain MRI and cerebrospinal fluid examination.6 The Colorado woman met diagnostic criteria required for the trial of natalizumab on clinical grounds alone, as did 91% of all trial participants.7 However, clinical trials in relapsing-remitting multiple sclerosis are mostly done in private practice settings and not by specialists in multiple sclerosis, and increasingly by non-neurologists. The accuracy of diagnostic criteria for multiple sclerosis in this setting is unknown, but—if the woman in Colorado is any indication—sensitivity and especially specificity may be poor. It is vital that entry criteria into clinical trials of relapsingremitting multiple sclerosis safeguard against the inclusion of patients with misdiagnosed migraine and cerebrovascular disease. The inclusion of such patients calls into question the validity of the results and exposes these patients to risks without any hope for benefit. These problems can be easily corrected by requiring objective evidence of CNS inflammation and demyelination at some point in a patient’s disease course before allowing drugs with unknown safety profiles to be tested on them. Even if the Colorado woman had had multiple sclerosis, she had a normal neurological examination at the time of entry into the trial, indicating that she was at low risk for developing disability.8–10 When designing entry criteria for clinical trials, we must ask ourselves who are we trying to treat and why? During the past decade, there have been two major changes in the way many clinicians view multiple sclerosis that have contributed to the development of lax entry criteria into clinical trials of relapsing-remitting multiple sclerosis. First, physicians have been led to believe that most patients with this disease will have a poor prognosis, and, second, that drugs work best if given early in the disease course. These shifts clearly benefit the drug companies, because they imply that all patients who might possibly have
Multiple sclerosis Coloured MRI scan of plaques (destroyed myelin; pink, arrowed). Healthy nerve tissue is yellow.
relapsing-remitting multiple sclerosis should be treated immediately. However, these views are not supported by what is known about the natural history of the disease. Disability in most patients with relapsing-remitting multiple sclerosis accumulates slowly, if at all, and there is no evidence that aggressive early treatment prevents long-term or even short-term disability. Thus the current sense of urgency to treat is inappropriate. At the onset of multiple sclerosis, two clinical subtypes can be readily identified: 85% of patients develop a relapsing-remitting course, whereas the other 15% develop progressive disability from the onset, with or without superimposed relapses (so-called primary progressive multiple sclerosis). Patients with primary progressive multiple sclerosis generally have a poor prognosis, and life-expectancy is reduced in this group. However, relapsing-remitting multiple sclerosis is a chronic life-long illness that is rarely fatal. Though one often cited study found that 95% of patients with multiple sclerosis will eventually develop clinically significant physical disability,11 this figure is a seriously biased estimate of the risk in relapsing-remitting multiple sclerosis. That cross-sectional study was done at a tertiary care clinic and 35% of participants had primary progressive multiple sclerosis. The risk of clinically significant disability reported in most other studies is much lower, ranging 709
Comment
from 35% to 60%.12–15 In the only prospective population-based cohort study with 25 years of followup, only 43% of the cohort progressed to needing a cane or worse.10 Under the new diagnostic criteria, the fraction of non-disabled patients is likely to increase.16 Though some have argued that a high proportion of these patients with so-called benign relapsing-remitting multiple sclerosis will develop clinically significant cognitive impairment, there is no evidence to support this claim.17 In fact, cognitive and physical disability are highly correlated.18 If the safety profile of a drug is unknown, enrolling participants who are likely to have a favourable disease course and are not clearly at risk of developing disability over 2 years (the length of most phase III trials in patients with relapsing-remitting multiple sclerosis) exposes patients to unnecessary risk. There are reliable predictors of prognosis that could be used to help separate those who might benefit from treatment from those for whom the risk of treatment probably outweighs the benefit. The best predictors of early and intermediate diseasecourse outcomes are incomplete recovery from attacks9,15,19–21 and accumulation of disability within the first 2–5 years after disease onset.8–10 Clinical trials of drugs with unknown safety profiles should aim to exclude patients with normal or nearnormal neurological examination and target those patients with relapsing-remitting multiple sclerosis at greater risk of disability, such as those with long duration of disease and a moderately abnormal neurological examination, or short duration of disease and at least a mildly abnormal neurological examination. Despite these concerns, the US Food and Drug Administration has allowed Biogen Idec and Elan to resume open-label natalizumab monotherapy trials in the same patients who met the lax entry criteria.22 We applaud the fact that the drug is only being used in the tightly monitored setting of a clinical trial. However, under these conditions, it is likely that other patients with benign or misdiagnosed multiple sclerosis will develop progressive multifocal leucoencephalopathy.
We thank Michael K Gould and Kristin Cobb for helpful reviews of the manuscript. AL-G was supported by grant NS43207-04 from the National Institute of Neurologic Disorders and Stroke. ALG has consulted for Genentech, Amgen, and Biogen Idec, and has been on a speaker’s bureau for Biogen Idec. LS has received support from the National Institutes of Health, the National MS Society, and the Phil N Allen Trust, and is a founder of Bayhill Therapeutics and Neurocrine Biosciences. 1
2
3
4
5 6
7 8
9
10 11
12
13
14
15
16 17
18
19
20
21
Annette Langer-Gould, *Lawrence Steinman Department of Health Research & Policy (AL-G) and Department of Neurology and Neurological Sciences (AL-G, LS), Stanford University School of Medicine, CA94305, USA [email protected]
710
22
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353: 369–74. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353: 375–81. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005; 353: 362–68. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227-31. Schumacker GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis: Ann N Y Acad Sci 1965; 122: 552–68. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–27. Bryan WW. Clinical Review; BLA 125104/0; Tysabri (natalizumab). Washington, DC: Food and Drug Administration, March 8, 2005: 37. Achiron A, Barak Y, Rotstein Z. Longitudinal disability curves for predicting the course of relapsing-remitting multiple sclerosis. Mult Scler 2003; 9: 486–91. Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003; 9: 260–74. Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116: 117–34. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I: clinical course and disability. Brain 1989; 112: 133–46. Pittock SJ, Mayr WT, McClelland RL, et al. Change in MS-related disability in a population-based cohort: a 10-year follow-up study. Neurology 2004; 62: 51–59. Myhr KM, Riise T, Vedeler C, et al. Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001; 7: 59–65. Kantarci O, Siva A, Eraksoy M, et al. Survival and predictors of disability in Turkish MS patients. Turkish Multiple Sclerosis Study Group (TUMSSG). Neurology 1998; 51: 765–72. Amato MP, Ponziani G, Bartolozzi ML, Siracusa G. A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci 1999; 168: 96-106. Black WC, Welch HG. Screening for disease. AJR Am J Roentgenol 1997; 168: 3–11. Pompeii LA, Moon SD, McCrory DC. Measures of physical and cognitive function and work status among individuals with multiple sclerosis: a review of the literature. J Occup Rehabil 2005; 15: 69–84. Lynch SG, Parmenter BA, Denney DR. The association between cognitive impairment and physical disability in multiple sclerosis. Mult Scler 2005; 11: 469–76. Trojano M, Avolio C, Manzari C, et al. Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events. J Neurol Neurosurg Psychiatry 1995; 58: 300–06. Bergamaschi R, Berzuini C, Romani A, Cosi V. Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis. J Neurol Sci 2001; 189: 13–21. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770–82. US Food and Drug Administration, Center for Drug Evaluation and Research. Questions and answers on Tysabri (natalizumab) regarding the lifting of the clinical hold. Feb 15, 2006: http://www.fda.gov/cder/ drug/ infopage/natalizumab_clinicalhold_ga.htm (accessed Feb 27, 2006).
www.thelancet.com Vol 367 March 4, 2006
regulatory regimens.24,25 This will be one of the most important debates to get right in contemporary public health.
11
Simon Chapman
13
University of Sydney, Sydney 2006, New South Wales, Australia [email protected]
14
12
SC is on the boards of the Cancer Council NSW and Action on Smoking and Health (Australia), and is editor of Tobacco Control. 1 2
3
4
5
6
7
8
9
10
Bero L. Implications of the tobacco industry documents for public health and policy. Annu Rev Public Health 2003; 24: 267–88. Hirschhorn N. Tobacco documents bibliography. Galen Digital Library, University of California at San Francisco, April 27, 2005: http://www. library.ucsf.edu/tobacco/docsbiblio.html (accessed Sept 29, 2005). Assunta M, Fields N, Knight J, Chapman S. Care and feeding: the Asian environmental tobacco smoke consultants program. Tob Control 2004; 13 (suppl 2): ii4–12. Chapman S, Carter SM. “We are anxious to remain anonymous”: the use of third party scientific and medical consultants by the Australian tobacco industry. Tob Control 2003; 12 (suppl 31): iii1–37. Fields N, Chapman S. Chasing Ernst Wynder: 40 years of Philip Morris efforts to influence a leading scientist. J Epidemiol Community Health 2003; 57: 571–78. Anonymus. B & W problem lab: how to better estimate future environment for tobacco industry and B&W growth. April 27, 1977: http://legacy.library.ucsf.edu/tid/kfr83f00 (accessed Sept 29, 2005). Philip Morris International. Smoking and health: a clear and consistent message. 2004: http://www.philipmorrisinternational.com/pages/eng/ smoking/S_and_H.asp (accessed Sept 29, 2005). British American Tobacco. Smoking and health. Aug 23, 2005: http:// www.bat.com/OneWeb/sites/uk__3mnfen.nsf/vwPagesWebLive/ ED9E7B3E9270D92880256BF40003317F?opendocument&SID=&DTC= (accessed Sept 29, 2005). Hammond D, Collishaw NE, Callard C. Secret science: tobacco industry research on smoking behaviour and cigarette toxicity. Lancet 2006; 367: 749–53. Bialous SA, Yach D. Whose standard is it, anyway? How the tobacco industry determines the International Organization for Standardization (ISO) standards for tobacco and tobacco products. Tob Control 2001; 10: 96–104.
15
16 17
18
19 20
21
22
23 24 25
Shiffman S, Pillitteri JL, Burton SL, Rohay JM, Gitchell JG. Smokers’ beliefs about “Light” and “Ultra Light” cigarettes. Tob Control 2001; 10 (suppl 1): i17–23. Henningfield J, Pankow J, Garrett B. Ammonia and other chemical base tobacco additives and cigarette nicotine delivery: issues and research needs. Nicotine Tob Res 2004; 6: 199–205. Chapman S. “Keep a low profile”: pesticide residue, additives, and freon use in Australian tobacco manufacturing. Tob Control 2003; 12 (suppl 3): iii45–53. Department of Health and Ageing, Australian Government. Australian cigarette ingredient information. 2004: http://www.health.gov.au/ internet/wcms/Publishing.nsf/Content/health-pubhlth-strateg-drugstobacco-ingredients.htm (accessed Sept 29, 2005). Webb W (Philip Morris). Status of Marlboro development program. July 12, 1984: http://legacy.library.ucsf.edu/tid/gmr98e00 (accessed Sept 29, 2005). King W, Borland R, Christie M. Way-out developments at BATCO. Tob Control 2003; 12: 107–08. Foulds J, Ramstrom L, Burke M, Fagerstrom L. Effect of smokeless tobacco (snus) on smoking and public health in Sweden. Tob Control 2003; 12: 349–59. Campbell-Johnson Ltd. A public relations strategy for the Tobacco Advisory Council. Nov 20, 1978: http://legacy.library.ucsf.edu/tid/ uus39e001984 (accessed Sept 29, 2005). Wynder EL, Hoffmann D. Reduction of tumorigenicity of cigarette smoke. JAMA 1965; 192: 88–94. DiFranza JR, Savageau JA, Rigotti NA, et al. Development of symptoms of tobacco dependence in youths: 30 month follow up data from the DANDY study. Tob Control 2002; 11: 228–35. Carter SM, Chapman S. Smoking, health and obdurate denial: the Australian tobacco industry in the 1980s. Tob Control 2003; 12 (suppl 3): iii23–30. Cummings KM, Morley CP, Hyland A. Failed promises of the cigarette industry and its effect on consumer misperceptions about the health risks of smoking. Tob Control 2002; 11 (suppl 1): i110–117. Vagg R, Chapman S. Nicotine analogues: a review of tobacco industry research interests. Addiction 2005; 100: 701–12. Borland R. A strategy for controlling the marketing of tobacco products: a regulated market model. Tob Control 2003; 12: 374 –82. Callard C, Thompson D, Collishaw N. Transforming the tobacco market: why the supply of cigarettes should be transferred from for-profit corporations to non-profit enterprises with a public health mandate. Tob Control 2005; 14: 278–83.
What went wrong in the natalizumab trials? A 42-year-old woman in Colorado had a history of intermittent episodes of neurological dysfunction and was diagnosed with relapsing-remitting multiple sclerosis. She was treated with interferon-1 alfa, but continued to have episodes of neurological dysfunction and was enrolled into a clinical trial of natalizumab, a novel immunomodulatory agent. Unfortunately, she was one of three patients who developed progressive multifocal leucoencephalopathy and she died.1–3 According to her case report, her autopsy revealed no evidence of multiple sclerosis. She had no objective evidence of central nervous system inflammation at any time: her spinal tap analysis at the time of diagnosis was normal, and she never had gadolinium-enhancing lesions on any of her multiple brain MRI scans.1 The clinical 708
history, brain imaging, and autopsy findings were more consistent with migraines and infarcts than with relapsing-remitting multiple sclerosis. Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Until recently, no reliable measure of CNS inflammation or demyelination existed. Diagnosis was therefore established on clinical criteria alone. Specifically, multiple sclerosis was defined by two unexplained episodes of neurological dysfunction separated in time and by neuroanatomical region, plus the presence of one or more objective neurological deficits on examination.4,5 These criteria were devised for research rather than clinical purposes, at a time when most multiple sclerosis trials were done at academic centres and, because of their www.thelancet.com Vol 367 March 4, 2006
Comment
www.thelancet.com Vol 367 March 4, 2006
Rights were not granted to include this image in electronic media. Please refer to the printed journal
Science Photo Library
vagueness, require clinical expertise in neurology and multiple sclerosis to use. Diagnostic criteria for multiple sclerosis have since been revised to reflect developments in technology and an improved understanding of disease pathogenesis. However, the revisions have only served to broaden the definition of multiple sclerosis, rather than improve the specificity of diagnosis. Physicians may now diagnose multiple sclerosis on the basis of either the old clinical criteria or when a single clinical attack is accompanied by objective evidence of CNS inflammation and demyelination on brain MRI and cerebrospinal fluid examination.6 The Colorado woman met diagnostic criteria required for the trial of natalizumab on clinical grounds alone, as did 91% of all trial participants.7 However, clinical trials in relapsing-remitting multiple sclerosis are mostly done in private practice settings and not by specialists in multiple sclerosis, and increasingly by non-neurologists. The accuracy of diagnostic criteria for multiple sclerosis in this setting is unknown, but—if the woman in Colorado is any indication—sensitivity and especially specificity may be poor. It is vital that entry criteria into clinical trials of relapsingremitting multiple sclerosis safeguard against the inclusion of patients with misdiagnosed migraine and cerebrovascular disease. The inclusion of such patients calls into question the validity of the results and exposes these patients to risks without any hope for benefit. These problems can be easily corrected by requiring objective evidence of CNS inflammation and demyelination at some point in a patient’s disease course before allowing drugs with unknown safety profiles to be tested on them. Even if the Colorado woman had had multiple sclerosis, she had a normal neurological examination at the time of entry into the trial, indicating that she was at low risk for developing disability.8–10 When designing entry criteria for clinical trials, we must ask ourselves who are we trying to treat and why? During the past decade, there have been two major changes in the way many clinicians view multiple sclerosis that have contributed to the development of lax entry criteria into clinical trials of relapsing-remitting multiple sclerosis. First, physicians have been led to believe that most patients with this disease will have a poor prognosis, and, second, that drugs work best if given early in the disease course. These shifts clearly benefit the drug companies, because they imply that all patients who might possibly have
Multiple sclerosis Coloured MRI scan of plaques (destroyed myelin; pink, arrowed). Healthy nerve tissue is yellow.
relapsing-remitting multiple sclerosis should be treated immediately. However, these views are not supported by what is known about the natural history of the disease. Disability in most patients with relapsing-remitting multiple sclerosis accumulates slowly, if at all, and there is no evidence that aggressive early treatment prevents long-term or even short-term disability. Thus the current sense of urgency to treat is inappropriate. At the onset of multiple sclerosis, two clinical subtypes can be readily identified: 85% of patients develop a relapsing-remitting course, whereas the other 15% develop progressive disability from the onset, with or without superimposed relapses (so-called primary progressive multiple sclerosis). Patients with primary progressive multiple sclerosis generally have a poor prognosis, and life-expectancy is reduced in this group. However, relapsing-remitting multiple sclerosis is a chronic life-long illness that is rarely fatal. Though one often cited study found that 95% of patients with multiple sclerosis will eventually develop clinically significant physical disability,11 this figure is a seriously biased estimate of the risk in relapsing-remitting multiple sclerosis. That cross-sectional study was done at a tertiary care clinic and 35% of participants had primary progressive multiple sclerosis. The risk of clinically significant disability reported in most other studies is much lower, ranging 709
Comment
from 35% to 60%.12–15 In the only prospective population-based cohort study with 25 years of followup, only 43% of the cohort progressed to needing a cane or worse.10 Under the new diagnostic criteria, the fraction of non-disabled patients is likely to increase.16 Though some have argued that a high proportion of these patients with so-called benign relapsing-remitting multiple sclerosis will develop clinically significant cognitive impairment, there is no evidence to support this claim.17 In fact, cognitive and physical disability are highly correlated.18 If the safety profile of a drug is unknown, enrolling participants who are likely to have a favourable disease course and are not clearly at risk of developing disability over 2 years (the length of most phase III trials in patients with relapsing-remitting multiple sclerosis) exposes patients to unnecessary risk. There are reliable predictors of prognosis that could be used to help separate those who might benefit from treatment from those for whom the risk of treatment probably outweighs the benefit. The best predictors of early and intermediate diseasecourse outcomes are incomplete recovery from attacks9,15,19–21 and accumulation of disability within the first 2–5 years after disease onset.8–10 Clinical trials of drugs with unknown safety profiles should aim to exclude patients with normal or nearnormal neurological examination and target those patients with relapsing-remitting multiple sclerosis at greater risk of disability, such as those with long duration of disease and a moderately abnormal neurological examination, or short duration of disease and at least a mildly abnormal neurological examination. Despite these concerns, the US Food and Drug Administration has allowed Biogen Idec and Elan to resume open-label natalizumab monotherapy trials in the same patients who met the lax entry criteria.22 We applaud the fact that the drug is only being used in the tightly monitored setting of a clinical trial. However, under these conditions, it is likely that other patients with benign or misdiagnosed multiple sclerosis will develop progressive multifocal leucoencephalopathy.
We thank Michael K Gould and Kristin Cobb for helpful reviews of the manuscript. AL-G was supported by grant NS43207-04 from the National Institute of Neurologic Disorders and Stroke. ALG has consulted for Genentech, Amgen, and Biogen Idec, and has been on a speaker’s bureau for Biogen Idec. LS has received support from the National Institutes of Health, the National MS Society, and the Phil N Allen Trust, and is a founder of Bayhill Therapeutics and Neurocrine Biosciences. 1
2
3
4
5 6
7 8
9
10 11
12
13
14
15
16 17
18
19
20
21
Annette Langer-Gould, *Lawrence Steinman Department of Health Research & Policy (AL-G) and Department of Neurology and Neurological Sciences (AL-G, LS), Stanford University School of Medicine, CA94305, USA [email protected]
710
22
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353: 369–74. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353: 375–81. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005; 353: 362–68. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227-31. Schumacker GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in multiple sclerosis: Ann N Y Acad Sci 1965; 122: 552–68. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–27. Bryan WW. Clinical Review; BLA 125104/0; Tysabri (natalizumab). Washington, DC: Food and Drug Administration, March 8, 2005: 37. Achiron A, Barak Y, Rotstein Z. Longitudinal disability curves for predicting the course of relapsing-remitting multiple sclerosis. Mult Scler 2003; 9: 486–91. Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003; 9: 260–74. Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116: 117–34. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I: clinical course and disability. Brain 1989; 112: 133–46. Pittock SJ, Mayr WT, McClelland RL, et al. Change in MS-related disability in a population-based cohort: a 10-year follow-up study. Neurology 2004; 62: 51–59. Myhr KM, Riise T, Vedeler C, et al. Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001; 7: 59–65. Kantarci O, Siva A, Eraksoy M, et al. Survival and predictors of disability in Turkish MS patients. Turkish Multiple Sclerosis Study Group (TUMSSG). Neurology 1998; 51: 765–72. Amato MP, Ponziani G, Bartolozzi ML, Siracusa G. A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci 1999; 168: 96-106. Black WC, Welch HG. Screening for disease. AJR Am J Roentgenol 1997; 168: 3–11. Pompeii LA, Moon SD, McCrory DC. Measures of physical and cognitive function and work status among individuals with multiple sclerosis: a review of the literature. J Occup Rehabil 2005; 15: 69–84. Lynch SG, Parmenter BA, Denney DR. The association between cognitive impairment and physical disability in multiple sclerosis. Mult Scler 2005; 11: 469–76. Trojano M, Avolio C, Manzari C, et al. Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events. J Neurol Neurosurg Psychiatry 1995; 58: 300–06. Bergamaschi R, Berzuini C, Romani A, Cosi V. Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis. J Neurol Sci 2001; 189: 13–21. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770–82. US Food and Drug Administration, Center for Drug Evaluation and Research. Questions and answers on Tysabri (natalizumab) regarding the lifting of the clinical hold. Feb 15, 2006: http://www.fda.gov/cder/ drug/ infopage/natalizumab_clinicalhold_ga.htm (accessed Feb 27, 2006).
www.thelancet.com Vol 367 March 4, 2006